Phytochemical Content and Pharmacological Potential of M. oleifera

Phytochemical Content and Pharmacological Potential of M. oleifera: History

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Subjects: Allergy

Contributor: Md Jamal Uddin

M. oleifera contains several bioactive phytochemicals including flavonoids and isothiocyanates; polyphenols, carotenoids, alkaloids, and terpenoids; and triterpenoids, moringyne, monopalmitic, di-oleic triglyceride, campesterol, stigmasterol, β-sitosterol, avenasterol, and vitamin A. These bioactive phytochemicals are found in M. oleifera roots, fruits, and seeds. These phytochemicals have medicinal properties which have been shown to be effective antioxidant, antimicrobial, inflammatory, and anti-carcinogenic agents. More studies are required to explore the role of bioactive phytochemicals specially in kidney diseases. M. oleifera also possesses a variety of pharmacological properties, which are closely associated with the presence of its bioactive compounds. Therefore, in the following section we highlighted the pharmacological potential of M. oleifera. M. oleifera showed pharmacological potential against some plausible factors such as oxidative stress, inflammation, fibrosis, and other pathologies responsible for kidney diseases.

Moringa oleifera
antioxidant
anti-aging
fibrosis

1. Oxidative Stress

Oxidative stress is caused by an imbalance between the excessive free radical generation and insufficient antioxidant defense [29,30]. It is frequently observed in CKD [31,32,33], and has become a diagnostic factor [34]. A number of studies documented that M. oleifera has antioxidative properties to protect and/or alleviate cellular damage (Table 1 and Figure 2). M. oleifera extracts and compounds, particularly quercetin, kaempferol, isothiocyanates, rutin, myricetin, ascorbic acid, and β-carotene, showed antioxidant potentials either via direct scavenging of free radicals [35].

Table 1. Summary on the protective effects of M. oleifera against kidney diseases.

Sl. No.	Experimental Model	Treatment Dose of Moringa Extract	Major Research Outcomes	Molecular Markers	Ref.
1	STZ-induced nephrotoxic male Wister rats	250 mg/kg b wt for 6 weeks	Amelioration of oxidative stress and inflammation	↓MDA and ROS ↑CAT, SOD, GSH, and GPx ↓TNF-α and IL-6	[36]
2	db/db mice	150 mg/kg/day for 5 weeks	Oxidative stress and inflammation	↓LDL ↓TNF-a, ↓IL-1b, ↓IL-6, ↓COX-2, and ↓iNOS	[20]
3	Ischemia-reperfusion induced Wistar rats	200 mg/kg for 7 days; 400 mg/kg, 7 days by flank incision	Oxidative stress	↓MDA, ↑PC, ↓AOPP, ↓NO, ↓H₂O₂, ↓GPx and GST, ↑GSH	[24]
4	CoCl₂-induced rats	Orally received 400 mg/kg bw/day for 6 weeks	Oxidative stress Inflammation and Apoptosis	↓MDA, ↓H₂O₂, ↓8-OHdG, ↓CRP, ↓MPO, ↓TNF-α, and ↓NO ↓TNF-α, and NO↓	[37]
5	Gentamicin (GENT) induced Wistar rats	Orally treated with 100, 200 and 400 mg/kg/day for 28 days	Oxidative stress	↓K⁺ level, ↓plasma creatinine, ↑Creatinine clearance, ↓MDA, ↑SOD	[23]
6	Nickel-induced Wistar rats	5% M. oleifera 10% M. oleifera 15% M. oleifera	Oxidative stress	↓plasma creatinine, ↓urea, and ↑potassium, ↑plasma level of sodium	[38]
7	Methotrexate (MTX)-induced Mice	300 mg/kg body weight, orally for 7 days	Oxidative stress Inflammation Apoptosis	↓urea and ↓creatinine, ↓total protein, ↓MDA, ↑SOD and ↑GSH, ↑HO-1, ↑Nrf-2 ↓NF-kB, ↓Caspase-9	[25]
8	Tilmicosin (Til) induced Sprague Dawley rats	400 or 800 mg/kg bw, by oral gavage for 7 days	Oxidative stress, inflammation	↓H₂O_2, ↓MDA, ↑SOD, ↑GPx, mRNA expression ↓TNF-α, ↓IL-1β	[39]
9	Hg-induced Male Wistar rats	1.798 mg/kg p.o three times per week for 21 days	Oxidative stress	↓MDA level, ↑SOD, and ↑CAT	[40]
10	TiO₂NPs induce male albino rats	Daily oral dose of 400 mg/kg b w for 60 days	Oxidative stress Inflammation	↓MDA, ↑SOD, ↑GSH, ↑GST,↑GPx, ↑Total thiol and ↑HO-1, ↑Nrf2 ↓KIM-1, ↓NF-кB, ↓TNF-α, and ↓HSP-70	[41]
11	NaF induced Oreochromis niloticus	6.1 mg/L for 8 weeks	Oxidative stress	↓MDA, ↑SOD, ↑CAT, ↑GSH, ↑GPx, ↑TAC	[42]
12	Gentamicin-induced (80 mg/kg) Rabbit	150 mg/kg body for 10 days, 300 mg/kg wt. for 10 days	Oxidative stress	↓Serum urea and creatinine levels, ↓LPO	[43]
13	Lead treated Male Wistar rats	500 mg/kg for 7 days	Oxidative stress	↓ROS, ↓LPP, ↓TPCC, ↓metal content,	[44]
15	Beryllium-induced rats	150 mg/kg daily for 5 weeks	Oxidative stress	↓LPO, ↑GSH, ↑antioxidant enzymes activities, ↑G-6-Pase activity	[45]
16	Arsenic-induced toxicity in rats	500 mg/kg, orally, once daily	Oxidative stress	↑ALAD, ↑GSH,↓ROS, ↑SOD, ↑Catalase, ↓GSSG	[46]
17	Heat stress (HS)-induced rabbits	100, 200, and 300 mg, 6 weeks	Inflammation	↑cortisol, ↑adrenaline, ↑leptin, ↓IFN-γ, ↓TNF-α, ↓urea, and ↓creatinine, ↓IL-10, ↑NK, and ↑Treg	[47]
18	ML-induced male Sprague Dawley rats	Orally 800 mg/kg bw 800 mg/kg bw	Oxidative stress, Inflammation Apoptosis	↓Total bilirubin, ↓direct bilirubin, ↓indirect bilirubin, ↓urea, and ↓creatinine ↑serum levels of protein, ↑albumin, ↑globulin, ↑GPx, and ↑CAT ↓KIM-1, and ↓TNF-α and ↑Bcl-2, ↓TIMP-1	[48]
20	Seabream (Sparus aurata)	10% M. oleifera 4 weeks	Inflammation	↓TGF-β and ↓TNF-α ↑ACH₅₀ and ↑lysozyme activities and ↑IgM level ↑ (lyso and c3), ↑ (occludin and zo-1)	[49]
21	APAP-treated mice	100 mg/kg of bw, 200 mg/kg bw	Oxidative stress, inflammation	↑SOD, ↑CAT and ↑GPx, ↓MDA, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓IL-10	[50]
22	Iodide injected Rabbit	50 mg/kg body weight, orally once daily for 27 sequential days	Oxidative stress	↓MDA, ↑GSH, ↓NO, ↓lipid peroxidation, ↓ROS	[51]
23	Glycerol induced rat	50 mg/kg and 100 mg/kg for 7 days	Oxidative stress Inflammation	↑SOD, ↑GST, ↑GP_X, ↑GSH ↓MPO, ↓Creatinine, ↓BUN, ↓NO ↓H₂O₂, ↓AOPP, ↓MDA, ↓PC,↑PT, ↑NPT,↓KIM-1 and ↓NF-ҝB	[52]
24	Salmonella-induced mice	14, 42 and 84 mg/kg/day for 28 days	Oxidative stress inflammation	↑HO-1, ↑SOD-2 ↑Nrf-2	[53]
25	STZ-induced rats	250 mg/kg and SRC. 42 days	Oxidative stress inflammation	↓LDL, ↑HDL, ↓CHOL, ↑ORAC ↓IL-6, ↓TNF-α, and ↓MCP-1	[54]
26	TGF-β-treated rat kidney fibroblast cells	10, 50, and 100 µg/mL	Fibrosis	↓Type I collagen, fibronectin, and PAI-1 ↓TβRII and Smad4, and phospho-ERK	[55]
27	Gentamicin-induced Wistar rats	28 days at graded doses of 100, 200 and 400 mg/kg	Nephrotoxicity	↓Creatinine and MDA ↑SOD	[23]

MDA, Malondialdehyde; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; STZ, streptozotocin (C8H15N3O7); GSH: glutathione; CAT, catalase; SOD, superoxide dismutase; GPx, Glutathione peroxidase; IL-1β, Interleukin 1 beta; COX-2, cyclooxygenase-2; iNOS, Inducible nitric oxide synthase; AOPP, advanced oxidation protein products; PC, protein carbonyls; NO, nitricoxide; H₂O₂, hydrogen peroxide; 8-OHdG, 8-hydroxy-2-deoxyguanosine; MPO, myeloperoxidase; CRP, C-reactive protein; MTX, methotrexate; HO-1, heme oxygenase-1; Nrf2, nuclear factor erythroid 2-related factor 2; TAC, total antioxidant capacity; LPP, lipid perioxidation products; TPCC, total protein carbonyl content; ALAD, delta-amino levulinic acid dehydratase; BUN, Blood urea nitrogen; KIM-1, transmembrane tubular protein; Bcl-2, B-cell lymphoma 2; TGF-β, transforming growth factor beta; CHOL, Cholesterol; ORAC, oxygen radical absorbance capacity; and APAP, acetaminophen. ↑, increased; ↓, decreased.

Methanol extract of M. oleifera reduced the oxidative stress in STZ induced male rats by lowering the production of MDA, ROS, LDL, and CHOL, which increase the risk of CKD [36,54]. Methanol extract also lowered the generation of MDA, AOPP, NO, H₂O₂, GPx, and GST, all of which induce oxidative stress in ischemia-induced Wistar rats [29]. Another study showed that metabolic extract reduced the levels of BUN and creatinine, and total protein is increased in CKD patients [42]. Ethanolic extract of M. oleifera inhibits oxidative stress and atherosclerosis in CKD by lowering LDL [20]. 8-OHdG causes oxidative stress to DNA and promotes cancer [56], ameliorated by the ethanolic extract of M. oleifera [56]. Ethanol extracts decrease the plasma creatinine level by enhancing the process of creatinine clearance [30]. Plasma sodium and potassium levels were raised after treating nickel-induced Wistar rats with ethanolic extract of M. oleifera [34]. Ethanolic extract detoxified plasma by reducing the bilirubin levels (indirect/direct), urea levels, etc., in ML-induced male Sprague Dawley rats [48]. HO-1 and Nrf2 expression were stimulated by leaf extract of M. oleifera at dosages of 300 and 400 mg/kg body weight, respectively [25,41]. Leaf extracts up-regulated the level of total thiol TiO₂NPs induced male albino rats, which play an important role in antioxidant protection [41]. Leaf extract of M. oleifera also downregulated the oxidative stress generating mediators in sodium fluoride (NaF)-induced Oreochromis niloticus, gentamicin-induced rabbit, and APAP-treated mice [23,42,57].

M. oleifera alcoholic extract reduced oxidative stress by lowering the lipid peroxidation, and ROS in iodide injected rabbits [51]. Furthermore, fermented leaf extract of M. oleifera boosts the antioxidant activity in bacteria-induced mice [53]. M. oleifera extract reduced the manifestation of MDA, indicating that the free radicle overproduction was reduced in both Tilmicosin and Hg induced rats. Abarikwu et al. showed that SOD level was increased after treatment with M. oleifera in tilmicosin induced rats [40]. Hydroalcoholic root extract raised blood sugar, antioxidant enzyme activities, and G-6-phase activities, which protect the kidney from nephropathy in Beryllium-induced rats [45]. Seed powder reduced free radical species, TPCC, metal content, and increased ALAD activity in lead-treated rats [57]. In arsenic-treated rats, seed powder of M. oleifera considerably increased antioxidant function including GSH, CAT, and ALAD [46].

2. Inflammation

The kidney is responsible for maintaining whole-body homeostasis. Kidney disease is characterized by inflammation as a major pathology [58,59,60]. Acute or chronic disease such as ischemia, toxins, or inflammation affects kidney tubules, causing kidney fibrosis that is associated with reduction of GFR in kidneys [61]. Kidney injury is linked to the production of cytokines levels, which prolongs the acute phase of kidney disease [62]. Moreover, chronic inflammation is regarded as a comorbid condition in CKD [63]. Many plants have an anti-inflammatory action through active substances such as hesperidin, diosmin, withaferin, fucoidan, thymoquinone, etc. [64,65,66,67]. Here, the anti-inflammatory effects of M. oleifera has been discussed. M. oleifera has been reported to exhibit strong inflammatory activity (Table 1 and Figure 3). Methanolic extract of M. oleifera reduced inflammation in STZ induced male Wister rats by down-regulating the tumor necrosis factor (TNF-α), IL-6, and MCP-1, an important chemokine [36,54]. Tang et al. investigated the effects of ethanolic extract of M. oleifera in metformin-induced mice and observed that the M. oleifera declines the production of inflammatory markers and the expression of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) by reducing the phosphorylation of mitogen-activated protein kinase (MAPK) pathway [20]. Ethanolic extract of M. oleifera down-regulates the inflammatory cytokines in CoCl₂-induced rats, including NO, which is involved in the pathogenesis of inflammation [37]. Leaf extract of M. oleifera inhibits inflammatory cytokines production and regulates the inflammation by inhibiting NF-kB [25]. It was also observed that inflammation in Tilmicosin (Til) induced rats was reduced by M. oleifera extracts [39]. M. oleifera leaf extract protects against interstitial kidney inflammation with fibrosis by down-regulating KIM-1 in TiO₂NPs induced male albino rats [41]. M. oleifera extract increases the secretion of cortisol, adrenaline, Treg cells, NK, and leptin, promoting anti-inflammatory cytokines and regulating the immune system [47]. M. oleifera treatment reduced the expression of KIM-1, TIMP-1, and TNF-α in ML-induced male Sprague Dawley rats [48]. TNF-α, an inflammatory cytokine that stimulates IL-1; IL-6, downregulated by M. oleifera in Seabream (Sparus aurata); and activated TGF-β, elicits anti-inflammatory effects [49]. M. oleifera also reduced the inflammatory cytokines in APAP-treated mice, where APAP induces AKI [50]. Fermented extract of leaves also reduces the Nrf2 in Salmonella-induced mice [53].

Moringa seed’s phytochemicals can reduce the production of nitric oxide (NO) and the gene expression of LPS-inducible iNOS and interleukins 1β and 6 (IL-1β and IL-6) compared to curcumin [68]. Flavonoids have been shown to be effective inhibitors of nitric oxide synthase type 2 (NOS-2) actions, and it also inhibits protein tyrosine kinase action that is involved in the NOS-2 expression at the molecular level [69,70,71]. Flower extract can cause the activation of pro-inflammatory proteins such as toll-like receptors. In the flowers, quercetin and kaempferol can inhibit the signal transducer and activator of transcription 1 (STAT-1) and the NF-κB pathways [72,73]. M. oleifera flowers contain 80% hydroethanolic, a potent agent of anti-inflammation in the NF-κB signaling pathway [74]. Scientists discovered that phenolic glycosides suppress inducible iNOS expression and NO production in mouse macrophage cells, as well as COX-2 and iNOS proteins [75,76]. Moringa extracts eventually down-regulate the inflammatory mediators because its seeds and flowers contain many bioactive compounds. Each of these compounds has its individual effects.

3. Fibrosis

Kidney fibrosis is defined as a radical harmful connective tissue deposition on the kidney parenchyma, which leads to renal dysfunction. Epithelial to mesenchymal transition (EMT) is the main mechanism of kidney fibrosis, and the TGFβ-1-SMAD pathway and hypoxia are known as the main modulator of EMT [32,77]. TGF-β-induced expression of fibronectin, type I collagen, and PAI-1 rat kidney fibroblast cells is reduced by M. oleifera extract [55]. Furthermore, moringa root extract selectively inhibited TGF-β-induced phosphorylation of SMAD4 and ERK expression. These results suggest that moringa root extract may reduce renal fibrosis by a mechanism related to its antifibrotic activity in rat kidney fibroblast cells. Oral administration of M. oleifera seed extract reduced CCl4-induced liver fibrosis in rats [78].

4. Other Pathologies Those Are Associated with Kidney Diseases

Autophagy has a critical role in kidney physiology and homeostasis [79], and, thus, its regulation is an important determinant of kidney diseases [61]. AKI or CKD causes mitochondrial damage, but damaged mitochondria begin to accumulate in response to these types of stimuli. Autophagy protects the kidney through the removal of ROS-producing mitochondria [80,81,82]. Apoptosis is a type of programmed cell death in which cells are killed by a controlled system. It is an energy-dependent complex process [83]. It contributes to develop AKI, even organ failure [84]. Ischemia/reperfusion (I/R) induces apoptosis or necrosis in the kidney and loss of tubular cells, leading to decreased GFR [85,86]. Renal tubular cells express cell surface ‘death receptors’ of TNF-α which is responsible for inducing apoptosis [87]. Also, ROS production in kidney disease is responsible for promoting apoptosis [86].

This entry is adapted from the peer-reviewed paper 10.3390/plants10122818

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